PROJECT SUMMARY: Hereditary sensory and autonomic neuropathies (HSAN) are a genetically diverse group of disorders. These disorders are not uncommon, and contribute to major disability from extremity pain, frequent ulcerations and amputations. Some varieties may also affect the central nervous system with dementia, hearing loss, and spinal cord involvements. Clinical heterogeneity between and within families leads to these conditions frequently being under diagnosed or wrongly diagnosed typically as primary acquired disorders. As part of a program to nurture the career development of a clinician-investigator, we propose to test the postulate that HSAN neuropathies are caused by genetic defects important in axon integrity. The causative mutation(s) are hypothesized to be either coding sequence alterations or dosage effect due to copy number change. Additionally, phenotypic variable expression is hypothesized to be related to copy number change in HSAN varieties. The conceptual framework of this proposal rests on our preliminary work identifying chromosomal localization in a large HSAN kindred with hearing loss and dementia. We have also collected many other HSAN kindreds available for analysis. Affected kindreds and a large number of sporadically affected individuals have undergone quantitative clinical testing for comparison. We will take advantage of next-generation sequencing combined with sequence capture of the targeted regions to identify the sequence alterations, and comparative genome hybridization array to identify copy number changes. We will also assess the possible copy number changes of the previously identified HSAN genes for other affected kindreds. This project is the first step towards understanding the molecular basis of these varieties of neurologic disorders, providing necessary training for investigating other inherited neuropathies and the foundation for downstream translational discoveries. The proposed project involves close interaction with the established mentor and co-mentors at an institution with a record of excellence in clinically relevant basic science research. The candidate has already demonstrated potential for independent patient-based laboratory research. With training in advanced technology, web bioinformatics applications and biostatistics provided by this project, the candidate will develop a successful independent research program in patient relevant translational research. PUBLIC HEALTH RELEVANCE: Project Narrative: The genetic cause of many forms of hereditary sensory and autonomic neuropathy is still unknown. Our research will result in the identification of causative genes and further understanding of molecular pathways involved in these disorders. The results from the present study will improve our knowledge of disease mechanism and our ability to diagnose, ultimately to provide effective treatments for patients with peripheral neuropathy.